Is being HER2 (Human Epidermal growth factor Receptor 2) negative a good prognosis for breast cancer?

Is HER2 Negative Good for Breast Cancer Prognosis?

HER2-negative status is generally favorable compared to untreated HER2-positive disease, but in the modern era of HER2-targeted therapies, HER2-positive breast cancer now has outcomes approaching those of hormone receptor-positive tumors, making HER2 status less of a prognostic marker and more of a predictive marker for targeted therapy eligibility. 1

Historical Context vs. Modern Era

Before HER2-Targeted Therapies

• HER2-positive breast cancer was definitively associated with worse prognosis, with 5-year overall survival of 63.4% compared to 83.0% in hormone receptor-positive patients (HR = 2.49, P < .001) 1
• HER2 amplification/overexpression was a marker of poor prognosis, associated with aggressive tumor behavior, higher recurrence rates, and increased mortality when untreated 2, 3
• Before trastuzumab approval, HER2 amplification was considered a poor prognostic factor in metastatic breast cancer 2

After HER2-Targeted Therapies

• HER2-positive disease treated with targeted therapies now has 5-year overall survival of 88.3% versus 90.4% in hormone receptor-positive patients (HR = 1.24, P = .17), with no statistically significant difference 1
• HER2-targeted therapies have dramatically altered the natural history of HER2-positive breast cancer, with overall survival approaching luminal subtypes 1
• HER2 positivity is no longer a marker of poor prognosis if access to HER2-targeted therapies is granted 1

Current Clinical Implications by Subtype

HER2-Negative, Hormone Receptor-Positive

• Generally favorable prognosis, particularly for favorable histologies (pure tubular, pure mucinous, pure cribriform) which should be HER2-negative to maintain favorable prognosis 2
• Treatment relies on endocrine therapy with chemotherapy added based on individual risk factors 2

HER2-Negative, Triple-Negative

• More aggressive behavior without targeted therapy options available for HER2-positive disease 2
• Approximately one-third of triple-negative tumors exhibit HER2-low expression (IHC 1+ or 2+/ISH not amplified), which may benefit from newer antibody-drug conjugates like trastuzumab deruxtecan 2

HER2-Positive (Treated)

• With modern HER2-targeted therapy, outcomes are now excellent and comparable to hormone receptor-positive disease 1
• Standard first-line therapy includes dual HER2 blockade with pertuzumab/trastuzumab plus taxane, followed by trastuzumab emtansine (T-DM1) in second line 4, 5
• 12-year overall survival rate of 79% with adjuvant trastuzumab versus 73% without (absolute gain of 6.5%) 2

Important Caveats and Pitfalls

Risk of Undertreatment

• Patients who are clinically HER2-negative but PAM50-HER2-enriched have worse outcomes (HR = 1.99, P = .009) because they do not receive HER2-targeted therapies despite potentially benefiting from them 1
• This represents a critical gap where molecular subtyping may identify patients who would benefit from HER2-targeted therapy despite negative conventional testing 1

Small Tumors (pT1a-b, Node-Negative)

• Even HER2-positive patients with very small tumors (pT1a-b) and node-negative disease have low risk of recurrence at 5 years 6
• However, in hormone receptor-positive disease with pT1a-b, N0 tumors, HER2 overexpression was still associated with worse disease-free survival (HR 5.1; 95% CI, 1.0 to 25.7) 6
• The decision to use trastuzumab in T1a-b tumors must balance cardiac toxicity risks with uncertain absolute benefits 2

Brain Metastases Consideration

• Approximately 50% of HER2-positive patients develop brain metastases over the course of their disease, even with improved systemic therapies 2
• This remains a significant challenge despite overall improved outcomes 2

Bottom Line for Clinical Practice

In 2025, HER2 status functions primarily as a predictive biomarker for treatment selection rather than a pure prognostic marker. HER2-negative disease avoids the need for HER2-targeted therapy and its associated cardiac toxicity monitoring, but HER2-positive disease with appropriate targeted treatment now achieves equivalent or superior outcomes 1. The key is ensuring accurate HER2 testing in accredited laboratories and appropriate access to HER2-targeted therapies when indicated 2.